We have been investigating the mechanism of action of diet-derived agents with estrogen-like activity. The biological effects of the isoflavones, genistein, daidzein and equol, present in soy foods, were studied. The results form the basis of two manuscripts. One has been submitted for publication and the other is under preparation. We screened other dietary factors for their ability to induce an estrogen- like response. Among the several compounds that we screened, we found that curcumin and tangeretin were able to stimulate the expression of the estrogen responsive pS2 mRNA. However, unlike the compounds we have studied so far, curcumin and tangeretin did not interact with the estrogen receptor. The addition of tamoxifen did not inhibit their effect on pS2, indicating that these agents did not mediate their action via the estrogen receptor. We are pursuing the mode of action of these two phytochemicals and examining the possible involvement of another intermediate in this pathway. Growth factors have been postulated to act as regulators of human breast cancer cell proliferation and as modulators of the mitogenic effects of estrogen and the inhibitory effects of antiestrogens. Since the regulation of TGF-beta expression appears to be important in the control of breast cancer proliferation, we were interested in examining the effect of phytochemicals on TGF-beta mRNA expression. Using the sensitive method of reverse transcription polymerase chain reaction (RT-PCR), we have quantitated the levels of TGF-beta1 in MCF-7 cells treated with either estradiol or genistein. In a collaborative project with Dr. Hursting, we have been feeding genistein to p53 knockout mice. The effect of genistein on the survival rate of the mice and the expression of TGF-beta1 and other cell cycle regulators will be analyzed in various tissues.